The novel monoclonal antibody gantenerumab cuts through the beta-amyloid plaques implicated in Alzheimer's disease, according to a small early phase study.

Action Points

Note that the accumulation of amyloid-beta peptides in the brain is thought to be an important event in the pathophysiology of Alzheimer's disease, and a number of therapeutic approaches are aimed at reduction of beta-amyloid levels.

Note that this small study suggests that gantenerumab reduces brain amyloid levels at least in part by inducing microglial phagocytosis followed by lysosomal degradation.

Point out that the study does not address the issue of whether any reduction in brain amyloid level translates into beneficial clinical outcomes.

The novel monoclonal antibody gantenerumab cuts through the beta-amyloid plaques implicated in Alzheimer's disease, according to a small, early phase study.

The higher of the two doses used showed the biggest reductions but came with some transient inflammation or edema where those reductions occurred in the brain, the group reported online in the Archives of Neurology.

However, "it is still unclear whether any reduction in brain amyloid level will translate into clinical efficacy," they warned in the paper.

Other monoclonal antibodies, such as bapineuzumab and solanezumab (LY2062430), that also bind to beta-amyloid protein like gantenerumab does, are in various stages of development.

But efficacy has been a major sticking point for anti-amyloid drugs in late-stage trials so far.

Bapineuzumab broke up amyloid plaques as hoped, but without slowing cognitive decline in any but the subgroup of patients without the genetic risk factor ApoE4.

Trials with semagacestat, which inhibits beta-amyloid production, were halted for worsening clinical outcomes despite a reduction in plaque accumulation.

The failure of beta-amyloid deposition inhibitors latrepirdine and tarenflurbil also has cast doubt on amyloid as a target.

Side effects also have been a concern, as an earlier anti-amyloid vaccine was abandoned due to inflammation of the brain and meninges in 6% of treated patients. Cerebral vascular edema has been seen with the various other agents as well.

Yet all hope isn't lost, noted neurologist Richard B. Lipton, MD, of Albert Einstein College of Medicine, New York City.

The problem may be not with amyloid as a target but with how or at what stage it has been targeted, he explained in an interview with MedPage Today.

"There's a lot we don't know about the cascade of events that leads from individual amyloid monomers, which may be neurotoxic, to the deposition of amyloid in the form of plaque and to its removal," he said. "It's possible that we may be removing the wrong form of amyloid."

Santarelli's group was optimistic, though, about gantenerumab, which they noted is now in phase II study to look for a clinical benefit in patients with prodromal Alzheimer's disease.

Their study included 16 mild-to-moderate Alzheimer's disease patients seen at three university medical centers who were randomized to IV gantenerumab or placebo every four weeks.

PET scans using a tracer for amyloid plaques -- the total signal from regional carbon 11–labeled Pittsburgh Compound B retention -- showed that over the course of treatment with up to seven infusions compared with baseline, amyloid levels:

Rose 11.0% with placebo

Rose 2.1% with 60-mg gantenerumab

Fell 9.4% with 200-mg gantenerumab

For the specific signal from this amyloid measure, mean treatment differences versus placebo appeared dose-dependent (P=0.03):

Ex vivo experiments with sections of brain incubated with microglia cells also showed a dose-dependent impact of the drug in beta-amyloid plaque reduction, which appeared to occur within hours of administration via effector cell-mediated phagocytosis.

Two patients in the higher-dose group had focal changes in MRI signal consistent with inflammation or vasogenic edema, often at the sites where they had the greatest reductions in amyloid levels.

Both patients also developed microhemorrhages, which were mildly symptomatic in one patient with headache, dizziness, gait instability, and tremor.

The inflammation or edema appeared to resolve after treatment was discontinued, though the amyloid reduction persisted at six months post-treatment.

"When plaques are dissolved rapidly, clearance mechanisms may get saturated with a possible result of vasogenic edema," Santarelli's group noted in the paper.

If so, this is most likely to occur in areas with greater amyloid clearance, "and both mechanisms may result in microhemorrhages," they added.

While pointing out that larger studies are needed to evaluate whether the drug is safe, Lipton noted that some degree of inflammation may actually be a positive.

"If the inflammatory response is mild, it's likely that response plays a role in helping remove amyloid from the brain," he told MedPage Today.

Cognitive tests showed no consistent effects of treatment or correlation with changes in amyloid levels, though the researchers suggested cautious interpretation due to small sample size and short treatment duration.

Also, amyloid levels weren't similar between placebo and treatment groups at baseline.

"Although statistical analysis methods were chosen to address these limitations, any conclusions are provisional in nature," the group warned.

The study was supported by F. Hoffmann-La Roche.

Santarelli and several co-authors reported being full-time employees of Roche/F. Hoffmann-La Roche, some with Roche stock or stock options.

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